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Probiotics' efficacy in paediatric diseases: which is the evidence? A critical review on behalf of the Italian Society of Pediatrics.
Martinelli, M, Banderali, G, Bobbio, M, Civardi, E, Chiara, A, D'Elios, S, Lo Vecchio, A, Olivero, M, Peroni, D, Romano, C, et al
Italian journal of pediatrics. 2020;(1):104
Abstract
During the last decade several paediatric studies have been published with different possible indications for probiotics, leading to a global increase of probiotics' market. Nevertheless, different study designs, multiple single/combined strains and small sample size still leave many uncertainties regarding their efficacy. In addition, different regulatory and quality control issues make still very difficult the interpretation of the clinical data. The objective of this review is to critically summarise the current evidence on probiotics' efficacy and safety on a different number of pathologies, including necrotizing enterocolitis, acute infectious diarrhoea, allergic diseases and functional gastrointestinal disorders in order to guide paediatric healthcare professionals on using evidence-based probiotics' strains. To identify relevant data, literature searches were performed including Medline-PubMed, the Cochrane Library and EMBASE databases. Considering probiotics strain-specific effects, the main focus was on individual probiotic strains and not on probiotics in general.
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Free Amino Acids in Human Milk: A Potential Role for Glutamine and Glutamate in the Protection Against Neonatal Allergies and Infections.
van Sadelhoff, JHJ, Wiertsema, SP, Garssen, J, Hogenkamp, A
Frontiers in immunology. 2020;:1007
Abstract
Breastfeeding is indicated to support neonatal immune development and to protect against neonatal infections and allergies. Human milk composition is widely studied in relation to these unique abilities, which has led to the identification of various immunomodulating components in human milk, including various bioactive proteins. In addition to proteins, human milk contains free amino acids (FAAs), which have not been well-studied. Of those, the FAAs glutamate and glutamine are by far the most abundant. Levels of these FAAs in human milk sharply increase during the first months of lactation, in contrast to most other FAAs. These unique dynamics are globally consistent, suggesting that their levels in human milk are tightly regulated throughout lactation and, consequently, that they might have specific roles in the developing neonate. Interestingly, free glutamine and glutamate are reported to exhibit immunomodulating capacities, indicating that these FAAs could contribute to neonatal immune development and to the unique protective effects of breastfeeding. This review describes the current understanding of the FAA composition in human milk. Moreover, it provides an overview of the effects of free glutamine and glutamate on immune parameters relevant for allergic sensitization and infections in early life. The data reviewed provide rationale to study the role of free glutamine and glutamate in human milk in the protection against neonatal allergies and infections.
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Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy.
Hausmann, O, Daha, M, Longo, N, Knol, E, Müller, I, Northrup, H, Brockow, K
Molecular genetics and metabolism. 2019;(1-2):84-91
Abstract
OBJECTIVE To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU). METHODS Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment. RESULTS Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption. CONCLUSIONS Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended.
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4.
Adverse reactions to orthodontic materials.
Sifakakis, I, Eliades, T
Australian dental journal. 2017;:20-28
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Abstract
Adverse effects can arise from the clinical use of orthodontic materials, due to the release of constituent substances (ions from alloys and monomers, degradation by-products, and additives from polymers). Moreover, intraoral aging affects the biologic properties of materials. The aim of this review is to present the currently identified major adverse effects of the metallic and polymeric components found in orthodontic appliances and materials. Corrosion in metallic orthodontic attachments releases metal ions, mainly iron, chromium, and nickel. The latter has received the greatest attention because of its reported potential for an allergic response. The formation of an oxide layer may inhibit the outward movement of ions, thereby acting as an obstacle for release. Titanium alloys have superior corrosion resistance than stainless steel. The efficiency of polymerisation is considered an essential property for all polymers. A poor polymer network is susceptible to the release of biologically reactive substances, such as bisphenol-A (BPA), which is capable of inducing hormone-related effects. The close proximity of a light-curing tip to the adhesive, pumice prophylaxis after bonding, indirect irradiation and mouth rinsing during the first hour after bonding may decrease BPA release. The adverse effects of some orthodontic materials should be considered during material selection and throughout orthodontic treatment, in order to minimise possible undesirable implications.
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Nutrition and Allergic Diseases.
Neerven, RJJV, Savelkoul, H
Nutrients. 2017;(7)
Abstract
The development of IgE-mediated allergic diseases is influenced by many factors, including genetic and environmental factors such as pollution and farming, but also by nutrition. In the last decade, substantial progress has been made in our understanding of the impact that nutrition can have on allergic diseases. Many studies have addressed the effect of breastfeeding, pre-, pro- and synbiotics, vitamins and minerals, fiber, fruit and vegetables, cow's milk, and n-3 fatty acids, on the development of allergies. In addition, nutrition can also have indirect effects on allergic sensitization. This includes the diet of pregnant and breastfeeding women, which influences intrauterine development, as well as breastmilk composition. These include the diet of pregnant and breastfeeding women that influences intrauterine development as well as breastmilk composition, effects of food processing that may enhance allergenicity of foods, and effects via modulation of the intestinal microbiota and their metabolites. This editorial review provides a brief overview of recent developments related to nutrition and the development and management of allergic diseases.
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Low-grade disease activity in early life precedes childhood asthma and allergy.
Chawes, BL
Danish medical journal. 2016;(8)
Abstract
Asthma and allergies are today the most common chronic diseases in children and the leading causes of school absences, chronic medication usage, emergency department visits and hospitalizations, which affect all members of the family and represent a significant societal and scientific challenge. These highly prevalent disorders are thought to originate from immune distortion in early childhood, but the etiology and heterogeneity of the disease mechanisms are not understood, which hampers preventive initiatives and makes treatment inadequate. The objective of this thesis is to investigate the presence of an early life disease activity prior to clinical symptoms to understand the anteceding pathophysiological steps towards childhood asthma and allergy. The thesis is built on seven studies from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) birth cohort examining biomarkers of disease activity in 411 asymptomatic neonates in cord blood (I-II), urine (III), exhaled breath (IV-V) and infant lung function (VI-VII) in relation to the subsequent development of asthma and allergy during the first seven years of life. In papers I-II, we studied cord blood chemokines and 25(OH)-vitamin D, which represent a proxy of the inborn immature immune system, the intrauterine milieu, and the maternal immune health during pregnancy. High levels of the Th2-related chemokine CCL22 and high CCL22/CXCL11 ratio were positively correlated with total IgE level during preschool age (II). This suggests an inborn Th2 skewing of the immune system in healthy newborns subsequently developing elevated total IgE antibodies, which is considered to increase the risk of asthma and allergies later in life. Additionally, deficient cord blood 25(OH)-vitamin D levels were associated with a 2.7-fold increased risk of recurrent wheeze at age 0-7 years (I). Together, these findings support the concept that early life immune programming in the pre-symptomatic era plays an essential role for promotion of or protection against asthma and allergies. Therefore, preventive initiatives to restore immune health, such as vitamin D supplementation, should be directed to the fetus and the earliest postnatal life. The eosinophil granulocyte has a major role in the allergic inflammatory cascade and eosinophilia is considered a hallmark of many allergic phenotypes. In paper III, we examined neonatal urinary biomarkers including eosinophil protein X (u-EPX), which is contained in the eosinophil granules. Elevated u-EPX in asymptomatic neonates was associated with development of allergic sensitization and nasal eosinophilia, but not with wheezing or asthma (III). These findings suggest the presence of an ongoing low-grade disease process in early life characterized by eosinophil activation prior to appearance of allergy-related conditions. In papers IV-V, we investigated perinatal and genetic predictors of neonatal fractional exhaled nitric oxide (FeNO) and the relationship between neonatal FeNO and wheezing later in child-hood. The a priori selected determinants encompassed asthma genetic risk variants, anthropometrics, demographics, socioeconomics, parental asthma and allergy, maternal smoking, paracetamol and antibiotic usage during pregnancy, and neonatal bacterial airway colonization. Among those, only the DENND1B risk allele and paternal history of asthma and allergy were associated with increased FeNO values (V) suggesting that raised FeNO in neonatal life is primarily an inherited trait. The neonatal FeNO levels were widely dispersed (1-67 ppb) and children with values in the upper quartile were at increased risk of recurrent wheezing in early childhood, but not persistent wheezing, reduced lung function or allergy-related endpoints (IV). This suggests that elevated neonatal FeNO represents an early asymptomatic low-grade disease process other than congenitally small airway calibre contributing to a transient wheezing phenotype. Reduced lung function in neonates is associated with wheezing and asthma proneness, but it is unknown if such host factor also confers a risk of acute bronchiolitis, which is considered an index event of asthma persisting into school age. In paper VI, we investigated neonatal forced flow, volume, and responsiveness to methacholine in relation to occurrence of acute severe bronchiolitis at age 0-2 years. Children developing bronchiolitis had a 2.5-fold increased bronchial responsiveness as neonates (VI) suggesting a preexisting joint propensity of the airways to react adversely to common respiratory viruses and to develop asthma. This finding proposes airway hyperresponsiveness as yet another marker of low-grade disease activity among asymptomatic neonates on a trajectory towards childhood asthma. In paper VII, we examined whether neonates with impaired pulmonary capacity also had signs of systemic inflammation prior to clinical symptoms. Reduced FEV0.5 was significantly associated with elevated serum hs-CRP and other blood inflammatory markers (VII) suggesting presence of systemic low-grade inflammation from the beginning of life. Chronic low-grade inflammation is a common nominator of virtually all the major non-communicable welfare diseases (NCDs) of modernity whereof asthma and allergies are the earliest debuting disorders. The novel finding of systemic low-grade inflammation among neonates at increased risk of asthma and allergy, therefore implies that exploring the origins of asthma and allergy may also unravel disease mechanisms involved in other NCDs. In conclusion, the series of papers presented in this thesis (I-VII) evidence the presence of a pre-symptomatic disease process measurable in several body compartments, which supports the notion of low-grade disease activity in early life as a generic trait among neonates developing asthma and allergy. This hypothesis piggybacking on single biomarker assessments could be enforced and refined by applying novel global omics approaches. In particular, metabolomic analyses of serum, urine, and airway lining fluid from neonates as well as neonatal VOC profiling of exhaled breath may facilitate a broader understanding of the early low-grade disease activity preceding clinical symptoms. Disentangling the introductory pathophysiological mechanisms and underlying endotypes of disease is paramount for generating successful preventive measures to alleviate the major global burden of asthma, allergy, and other NCDs of modern time.
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Maternal and cord blood vitamin D status and childhood infection and allergic disease: a systematic review.
Fried, DA, Rhyu, J, Odato, K, Blunt, H, Karagas, MR, Gilbert-Diamond, D
Nutrition reviews. 2016;(6):387-410
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Abstract
CONTEXT It is unclear how in utero vitamin D deficiency affects the extraskeletal health of children, despite the known risks for adverse pregnancy/birth outcomes. OBJECTIVE This systematic review seeks to assess the effect of in utero vitamin D exposure on childhood allergy and infection outcomes using the PRISMA guidelines. DATA SOURCES MEDLINE, Cochrane Library, and Web of Science databases were searched. STUDY SELECTION Literature published through April 2015 was searched for studies reporting on the association between maternal pregnancy or cord blood vitamin D status and childhood allergy and infection. DATA EXTRACTION Of 4175 articles identified, 43 studies met the inclusion criteria. They examined a wide variety of outcomes, using many different vitamin D cutoff values in their analyses. DATA SYNTHESIS For most outcomes, results were inconsistent, although there appeared to be a protective effect between higher in utero vitamin D status and childhood lower respiratory tract infection (5 of 10 studies). CONCLUSIONS More research is needed on childhood allergy and infection outcomes, and future studies should standardize outcome reporting, especially with regard to cutoff values for vitamin D concentrations. Evidence of a protective association between in utero vitamin D exposure and lower respiratory tract infection was found, while the other outcomes were either understudied or showed inconsistent results.PROSPERO registration no. CRD42013006156.
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Childhood allergies and asthma: New insights on environmental exposures and local immunity at the lung barrier.
Smits, HH, van der Vlugt, LE, von Mutius, E, Hiemstra, PS
Current opinion in immunology. 2016;:41-47
Abstract
While certain bacteria and respiratory viruses promote local inflammation and disease onset, a more diverse colonization of the different species in the (gut) microbiome may be linked to more regulatory responses and protection against asthma and allergies. These processes are also influenced in part by food intake, both targeting the composition of the gut microbiome and influencing the immune system via metabolites. Early life environmental microbial exposure also contributes to protection against asthma and allergy and is linked with an early activation of the innate immune system and the development of regulatory immune responses. Although greater mechanistic insight is needed, it is tempting to speculate that part of the environmental effect can be explained by modulation of the microbiome composition at mucosal surfaces, epithelial barrier function and/or local immunity. A review of the latest studies is provided.
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Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders.
Theoharides, TC, Tsilioni, I, Patel, AB, Doyle, R
Translational psychiatry. 2016;(6):e844
Abstract
Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood-brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1β), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFβ induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.
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Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood.
Gunaratne, AW, Makrides, M, Collins, CT
The Cochrane database of systematic reviews. 2015;(7):CD010085
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Abstract
BACKGROUND Allergies have become more prevalent globally over the last 20 years. Dietary consumption of n-3 (or omega 3) long chain polyunsaturated fatty acids (LCPUFA) has declined over the same period of time. This, together with the known role of n-3 LCPUFA in inhibiting inflammation, has resulted in speculation that n-3 LCPUFA may prevent allergy development. Dietary n-3 fatty acids supplements may change the developing immune system of the newborn before allergic responses are established, particularly for those with a genetic predisposition to the production of the immunoglobulin E (IgE) antibody. Individuals with IgE-mediated allergies have both the signs and symptoms of the allergic disease and a positive skin prick test (SPT) to the allergen. OBJECTIVES To assess the effect of n-3 LCPUFA supplementation in pregnant and/or breastfeeding women on allergy outcomes (food allergy, atopic dermatitis (eczema), allergic rhinitis (hay fever) and asthma/wheeze) in their children. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 August 2014), PubMed (1966 to 01 August 2014), CINAHL via EBSCOhost (1984 to 01 August 2014), Scopus (1995 to 01 August 2014), Web of Knowledge (1864 to 01 August 2014) and ClinicalTrials.gov (01 August 2014) and reference lists of retrieved studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) evaluating the effect of n-3 LCPUFA supplementation of pregnant and/or lactating women (compared with placebo or no treatment) on allergy outcomes of the infants or children. Trials using a cross-over design and trials examining biochemical outcomes only were not eligible for inclusion. DATA COLLECTION AND ANALYSIS Two review authors independently assessed eligibility and trial quality and performed data extraction. Where the review authors were also investigators on trials selected, an independent reviewer assessed trial quality and performed data extraction. MAIN RESULTS Eight trials involving 3366 women and their 3175 children were included in the review. In these trials, women were supplemented with n-3 LCPUFA during pregnancy (five trials), lactation (two trials) or both pregnancy and lactation (one trial). All trials randomly allocated women to either a n-3 LCPUFA supplement or a control group. The risk of bias varied across the eight included trials in this review with only two trials with a low risk of selection, performance and attrition bias.N-3 LCPUFA supplementation showed a clear reduction in the primary outcome of any allergy (medically diagnosed IgE mediated) in children aged 12 to 36 months (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.98; two RCTs; 823 children), but not beyond 36 months (RR 0.86, 95% CI 0.61 to 1.20; one RCT, 706 children). For any allergy (medically diagnosed IgE mediated and/or parental report), no clear differences were seen in children either at 12 to 36 months (RR 0.89, 95% CI 0.71 to 1.11; two RCTs, 823 children) or beyond 36 months of age (RR 0.96, 95% CI 0.84 to 1.09; three RCTs, 1765 children).For the secondary outcomes of specific allergies there were no clear differences for food allergies at 12 to 36 months and beyond 36 months, but a clear reduction was seen for children in their first 12 months with n-3 LCPUFA (both for medically diagnosed IgE mediated and medically diagnosed IgE mediated and/or parental report). There was a clear reduction in medically diagnosed IgE-mediated eczema with n-3 LCPUFA for children 12 to 36 months of age, but not at any other time point for both medically diagnosed IgE mediated and medically diagnosed IgE mediated and/or parental report. No clear differences for allergic rhinitis or asthma/wheeze were seen at any time point for both medically diagnosed IgE mediated, and medically diagnosed IgE mediated and/or parental report.There was a clear reduction in children's sensitisation to egg and sensitisation to any allergen between 12 to 36 months of age when mothers were supplemented with n-3 LCPUFA.In terms of safety for the mother and child, n-3 LCPUFA supplementation during pregnancy did not show increased risk of postpartum haemorrhage or early childhood infections. AUTHORS' CONCLUSIONS Overall, there is limited evidence to support maternal n-3 LCPUFA supplementation during pregnancy and/or lactation for reducing allergic disease in children. Few differences in childhood allergic disease were seen between women who were supplemented with n-3 LCPUFA and those who were not.